It is desirable to find new bronchodilating agents, which have more potent activity and less side effects than the drugs which are available on the market. The compounds of the general structural formula
are examples of presently preferred long acting bronchodilator drugs on the market. The bronchodilator terbutaline (Z=H) is one such drug. Bambuterol (Z=C(O)NMe2), the bis-dimethylcarbamate prodrug of terbutaline, has more potent bronchospasmolytic activity than the latter upon oral administration and exhibits a duration of activity of more than 12 hours. Bambuterol also exhibits a lower degree of undesired cardiovascular side effects. In addition, Bambuterol has lipid lowering effects in certain patients. (Bauer CA and Svensson LA, EP 0521967, 1990).
It is known that among many drugs having chiral centers, one enantiomer of a racemic pair is often more active than the other in treating a medical condition. For example, the levorotatory R-enantiomer of albuterol is approximately 80 times more potent as a β-2 receptor agonist than the dextrorotatory S-enantiomer (Hartley and Middlemis, J. Med. Chem., 14, 895-896, 1971), and the administration of the pure R-enantiomer offers improved therapeutic activity and fewer side effects. The United States Food and Drug Administration has approved R-albuterol hydrochloride as a new drug for the treatment of asthma. Similar results in vivo were obtained with enantiomer of terbutaline.(Kallstrom et al., Chorality 1996,8,567).
The prodrug of terbutaline, bambuterol, has a chiral center, and it can exist as a racernic mixture or as pure enantiomeric forms (Torsten et al,. U.S. Pat. No. 4,419,364, 1983). To our knowledge, no method to resolve racemic bambuterol has been discovered or published, nor has a single enantiomer of bambuterol been prepared. Thus, the biological properties and therapeutic role of either R or S bambuterol have not been studied. Racemic bambuterol has been marketed and widely used clinically for several years. It is known that the S-isomers of β-2 agonists—including terbutaline—are more toxic or less potent than the R-isomers, properties which may be responsible for the side effects of racemic bambuterol in its clinical use. The present invention teaches the preparation of single enantiomers of bambuterol of high purity, and the superior therapeutic benefits of the single R-enantiomer of the drug over racemic bambuterol.
At least two synthetic approaches have been employed to control the stereochemistry of the chiral center of albuterol and related 2-phenylethanolamines. One approach utilized in the preparation of the enantiomerically pure R and S forms of albuterol is resolution of a racemic mixture of an intermediate in its synthesis or of the final compound itself (for review see Bakale et al., Clinical Reviews in Allergy and Immunology, Vol. 14, pp 7-35, 1996). The second approach involves asymmetric synthesis, which is the de novo synthesis of a chiral substance from chiral precursors.